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Germline CDK12 variants in aggressive prostate cancer

Sofie H Tolmeijer1, Corinne Maurice-Dror2, Shahneen Sandhu3

  • 1University of British Columbia Vancouver, British Columbia Canada.

Cancer Discovery
|July 2, 2026
PubMed

Insights

Rare germline CDK12 variants drive lethal metastatic prostate cancer (mPCa). These inherited mutations, found in 0.1% of patients, lead to a specific genomic instability signature and are linked to family cancer histories.

Area of Science:

  • Genetics
  • Oncology
  • Genomic Instability

Background:

  • CDK12 mutations are found in 2-7% of metastatic prostate cancer (mPCa) and were previously thought to be exclusively somatic.
  • Germline variants are rare genetic alterations inherited from parents.

Purpose of the Study:

  • To investigate the role of germline CDK12 truncating variants in metastatic prostate cancer.
  • To determine the frequency and clinical significance of germline CDK12 variants in mPCa.

Main Methods:

  • Screening of 4,535 metastatic prostate cancer patients for germline CDK12 truncating variants.
  • Analysis of tumor genomes for secondary somatic CDK12 variants and genomic instability signatures.
  • Comparison of germline variant frequency with large population control cohorts (gnomAD).
  • Pedigree analysis to confirm germline variant inheritance.

Main Results:

  • Identified five mPCa patients (0.1%) with germline CDK12 truncating variants.
  • All patients exhibited CDK12-driven cancers with a distinct genomic instability signature (tandem duplications).
  • Germline CDK12 variants were significantly enriched in mPCa compared to controls.
  • Family histories and pedigree analyses confirmed inheritance patterns and links to prostate and ovarian cancers.

Conclusions:

  • Germline CDK12 truncating variants are a rare but significant driver of lethal metastatic prostate cancer.
  • These variants contribute to a specific genomic instability phenotype.
  • Germline CDK12 testing may have implications for risk assessment and family cancer counseling.

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